Definition of paraneoplastic syndromes in Robbin's Basic Pathology:
The most common biologically active substance secreted from carcinoid tumors is 5-HT (serotonin), a vasoactive peptide whose biosynthesis is accomplished nearly exclusively by the enterochromaffin cells. Synthesized from the amino acid tryptophan, the release of 5-HT into the systemic circulation can cause the classic symptoms of the carcinoid syndrome, which include diarrhea, episodic flushing, bronchoconstriction, and eventual right-sided valvular heart disease
Cytokines play a major role in cancer cachexia.
In fact, replacement of nutrition may not reverse the cachexia. Source
#psychiatry
Monoamine theory of depression.
It has been theorized that depression results from a deficiency of monoamine neurotransmitters.
Monoamine neurotransmitters include serotonin (5-HT) and noradrenaline.
SSRI: Fluoxetine, sertraline, citalopram, escitalopram
TCA: clomipramine, imipramine, amitriptyline
Newer, mixed 5-HT and noradrenaline reuptake inhibitors (SNRI) : venlafaxine, duloxetine. (less selective for 5-HT than SSRIs)
Noradrenaline reuptake inhibitors : bupropion, atomoxetine
St. John's wort - weak monoamine uptake inhibitor.
Mirtazapine
Irreversible non competitive : phenelzine
Reversible MAO-A selective - moclobemide.
#2022BSQ-NOW Q32
Serotonin (aka 5-hydroxytryptamine(5-HT) is a monoamine neurotransmitter.
Serotonin has diverse effects. ]
Stimulation of the postsynaptic 5-HT1A and 5-HT2A receptors has been implicated in serotonin syndrome.
Serotonin toxicity (increased serotonin activity in the CNS) in the brain.
Commonest with MAOIs.
SSRIs have less potential for SS but still cause it.
SNRIs have higher potential for SS than SSRIs.
Life threatening!.
The syndrome is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin.
It is a Clinical diagnosis. No laboratory testing available.
Classically described as a tried of
Highly suggestive features (based on the groups above): (based on Hunter criteria for diagnosis)
| Saturation kinetics at high dose | First order kinetics |
[[2022 May Basic Sciences#Cholera vaccine|Cholera vaccine]]
#TODO
Treatment of malaria in #pregnancy
Full house pattern only means activation of complement pathway: it's not specific for SLE.
Nephrotic syndrome (MMF)
Nephritic syndrome (= glomerulonephritis)
Mixed nephritic / nephrotic pictures
Asymptomatic haematuria and / or proteinuria
MCD / Membranous / FSGS => ''MMF''
Children: Commonest cause is minimal change disease
Adults: 30% have systemic disease :
Remainder
Only rarely leads to CKD.
Membranous nephropathy -
Clinical
Membranous nephropathy is the one most likely to occur secondary to a cancer. (i.e paraneoplastic) - PasTest
[!TIP] Haematuria with associated Proteinuria suggest glomerulonephritis rather than macroscopic bleed.
(I.e renal biopsy is more suitable than cystoscopy)
FSGS recurs in transplanted kidneys.
| Primary FSGS | Secondary FSGS |
| -------------------------------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------- |
| Sometimes responds to steroids, failure of steroids is common. Other immunosuppresants are used. | Usually poor response to steroids. ACEi are better |
| Presents as massive proteinuria, haematuria and hypertension. | Can be caused by any process which reduces functioning number of nephrons (eg. nephrectomy) |
| | (nephrectomy, hypertension, gross obesity, IgA nephropathy, HIV, CMV, EBV) |
[!TIP]
MCD and FSGS are like cousins; similar but different
Haematuria is commoner in FSGS than in MCD.
MCD shows selective protein loss -> i.e mainly albumin and not higher molecular weight proteins like immunoglobulins. FSGS shows non-selective proteinuria.
FSGS shows poor response to corticosteroids.
Higher percentage of FSGS patients go on to develop CKD (50%). (adults have worse prognosis)
MCD and FSGS both show minimal / no immune deposits.
FSGS : FSGS changes on light microscopy. MCD: few changes visible on light microscopy.
mixed nephrotic / nephritic picture. => nephrotic Xn + haematuria, hypertension and impaired renal function
Most patients will go on to develop ESKD over several years;
recurs in renal transplant patients.
C3 complement levels are low.
Type 1 <= activation classical complement pathway - low C3 levels, normal C4 levels. (Tramline pattern seen)
Type 2 <= activation of alternative complement pathway
Neuro: if severe, tonic clonic seizure and coma.
There is no hepatitis C vaccine.
The commonest contraindications for vaccination are
Zoster vaccine is recommended for persons 60 years of age or older. This vaccine is similar to the varicella vaccine, except that the titer of virus is ~14-fold higher. The vaccine is about 50% protective in preventing zoster and 66% effective in preventing postherpetic neuralgia. - ScienceDirect snippet
VARICELLA ZOSTER = VIRUS
HERPES ZOSTER = SHINGLES
Neisseria meningitides is on of the few gram -ve cocci that we have to worry about. Source
They are commensals in the throad of upto 10% of people.
It is spread by close contact with sharing of respiratory or throat secretions.
In some people, risk factors such as predispose to infection.
When a patient gets Meningococcal infection, close contacts should receive prophylaxis. (Drinking from the same bottle, smoking the same cigarette, sharing utensils etc. does not constitute close contact).
The risk of developing the disease for household contacts exposed to patients who have sporadic meningococcal disease was estimated to be 4:1000 exposed people, which is 500 to 800 times greater than the risk for the total population
Source
Neisseria meningitidis is unique among major causes of bacterial meningitis for its ability to cause endemic and epidemic disease. Serogroup A is the commonest cause of large epidemics. Serogroup C causes endemic disease Source
There are 3 types of vaccines
Vaccination is recommended only for persons with specific high risk conditions including complement deficiency, anatomic or functional asplenia or for those who have had contacts with infected patients.
Vaccination is used for close contacts of patients with meningococcal disease due to A, C, Y, or W135 serogroups, to prevent secondary cases.- MedScape
Treatment:
Rifampicin, ciprofloxacin and ceftriaxone are effective in treatment of N. meningitides infection.
Hypertensive emergency = hypertension (usually SBP > 180 / DPB > 120) with associated end organ damage.
Otherwise, it's just asymptomatic hypertension.
[!TIP] Need to exclude cause of secondary hypertension
Secondary causes of hypertension are more common in patients who have a hypertensive emergency compared with other hypertensive populations.
Aim to reduce MAP
| Condition | SBP - Target | Duration |
|---|---|---|
| Isch Stroke + repferfusion | 185 | |
| Isch Stroke - repferfusion | 220 | |
| Aortic dissection | 100 | 20 min |
| H'rragic stroke - very high BP | 220 | rapid |
| H'rragic stroke - high BP | 140 | 1 hour |
| Drug | mechanism | Comments |
|---|---|---|
| SNP | NO -> cAMP -> K+ channels stimulated -> SM relaxation of arterioles and veins | Onset: 1 min, Duration 10 min. Caution! : rapid hypotension; contraindicated in #pregnancy |
| SNP can decrease renal, cerebral and coronary perfusion; potential for cyanide poisoning | ||
| GTN | Same mechanism; | Similar pharmacokinetics; venodilation >> arteriolar dilation; reflex tachcardia; |
| Useful in patients with symptomatic coronary artery disease | ||
| Clevidipine | Ultrashort acting dihydropyridine CCB given parenterally. | |
| Nicardipine | IV dihydropyridine CCB. | |
| Fenoldopam | Dopamin agonist. Increases renal perfusion while lowering BP | Good in patients with renal failure. |
Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular cells : Medullary CA.
[!INFO] Hot nodules are almost always noncancerous
They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically
Hürthle cell carcinoma is a variant of follicular carcinoma and makes up 2-3% of all thyroid malignancies
Osteoblastic:
Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source
Source: CVS physiology website.
| presentation | Abdominal pain + perianal disease. (although colonic disease can cause PR bleeding) | GI bleeding |
| Pathology | Transmural involvement(+) (wall to serosa), Granulomas (+) | mucosal and submucosal inflammation |
#2022BSQ Q5
[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.
ONLY TAENIA SAGINATA causes CYSTICERCOSIS.
Probably the most common parasitic infection of the CNS.
Pigs are the usual intermediate host, Humans are the definitive host.
cysticercosis results from humans acting as accidental intermediate hosts for the parasite
[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.
Now found that most infections are asymptomatic. However, people infected with cysticercosis usually present due to the neurological symptoms.
Seizures are very common.
Diagnosis: Combintion of imaging and serology are required because there are situations in which only one of the two modalities will show positive results.
Imaging : MRI or CT, Serology: Immunoblot / enzyme linked assasy
Treatment:
Treatment of neurological symptoms with anticonvulsants, reducing cerebral oedema, intracranial pressure etc is the main concern.
Then, cysts are treated if required.
Calcified cysts are dead; antihelminthic therapy won't benefit the patient.
Live cysts: Antihelminthing treatment must be combimed with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite.
Histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease
monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage
| Disease | Pattern |
|---|---|
| Tuberculosis | Caseating (i.e absolutely no cellular structure) granuloma with occasional Langhans giant cells |
| Leprosy | Non caseating granuloma |
| Sarcoidosis | Non caseating, abundant activated macrophages |
| Cat Scratch disease | Rounded or stellate, central debris present. |
| Syphillitic gumma | Central necrosis but with preserved cell outlines, plasma cell infiltrate |
| GPA (granulomatosis with polyangitis) | presence of multinucleated giant cells, interstitial collagen alteration, and the presence of a polymorphous inflammatory infiltrate |
[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
There membranes beging to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.
#2022BSQ Q2
Routes of malignant spread
Primary brain tumours are either
Source:Medscape
Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce calcitonin).
[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold**.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.
Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.
Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.
Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.
Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
No special nuclear features.
Differentiated from benign adenomas by
They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically
Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.
Distant mets for both types occur to lung and bone.
Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.
2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.
Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.
Familial cases are multifocal.
Sporadic cases are unifolcal.
FMTC syndromes:
In adults, bone mets are far more common than primary bone tumours.
Bone is the 3rd commonest site of metastatis next to Lung and liver.
Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).
Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma
Bone mets are commonest in spine, pelvis and thigh.
Osteolytic :
Osteoblastic:
Ignore breast in this list!
Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source
Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.
Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.
Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present
Renal cancer also commonly spreads to bone.
#2022BSQ Q8
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.
Atherosclerosis requires two factors
Anything that exacerbates these two factors will promote atherogenesis.
In the presence of lipids within the intima, macrophages become activated. When they engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.
Plaques can
Factors which make a plaque unstable:
#2022BSQ Q24
Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent
Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.
#2022BSQ Q24
See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasolidation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon
Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)
GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.
Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source
Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source
Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.
[!TIP] All of these hormones generally cause changes which promote digestion and absorption except for somatostatin
CT
[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.
#2022BSQ Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eleminated by the Reticuloendothelial system. Serum level isn't elevated in kidney disease.
3 isoforms
Skeletal muscle - 99% CK MM
CK-MB = Usually in cardiac muscle. Can also be elevated in elite athletes and normal people after strenuous exercise (i.e can produce false +ve for MI)
CK is usually elevated in myopathies. => there are different types of myopathies
Can also be elevated in a few non myopathic conditions
We went to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.
Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!
Sample is cooled until it is send to the lab to prevent bacterial multiplication affecting the colony count.
8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.
White blood cell casts - renal infection = could be pyelonephritis.
Causes of sterile pyuria:
Source: CVS physiology website.
| pacemaker cells | non pacemaker cells |
|---|---|
| No true resting potential | |
| Continuous action potentials generated | |
| Depolarization due to SLOW calcium current | FAST Na mediated depolarization |
Hyperkalemia
EKG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest. These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.
Hypokalemia
EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave.
The U-wave is a deflection following the T wave. Hypokalemia causes enlarged and prominent T waves on the EKG. Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.
Hypercalcaemia
The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.
Hypocalcemia
The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563
doi.org/10.1016/0002-9149(63)90255-8
Hypermagnesaemia
[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:
- Prostate-Specific Antigen (PSA) - Prostate cancer
- Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
- Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
- CA-125 - Ovarian cancer
- CA 19-9 - Pancreatic cancer, colorectal cancer
- CA 15-3 - Breast cancer
- CA 27-29 - Breast cancer
- Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
- Calcitonin - Medullary thyroid cancer
- Thyroglobulin - Thyroid cancer (papillary and follicular)
- Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
- Chromogranin A - Neuroendocrine tumors
- S-100 Protein - Melanoma, neuroendocrine tumors
- Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
- Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
- 5 HIA - carcinoid tumour
- Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.
BRCA1 and BRCA2 - breast and ovarian cancer.
[!TIP] A great summary!
Source
[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's
| Feature | Crohn's Disease | Ulcerative Colitis |
|---|---|---|
| presentation | Abdominal pain + perianal disease. (although colonic disease can cause PR bleeding) | GI bleeding |
| Endoscopy | Cobblestones + linear ulcers | Diffuse continuous involvement, pseudopolyps |
| Radiography | Fistulae | No fistulae |
| Distribution | (potentially mouth to anus) Terminal ileal involvement Or ileocolitis, skip lesions(+) | No ileal involvement (backwash ileitis possible) |
| Rectal involvement | Possible, may spare the rectum | Rectum always involved |
| Pathology | Transmural involvement(+) (wall to serosa), Granulomas (+) | mucosal and submucosal inflammation |
| Serositis(+) | Crypt abscesses – Crypt abscesses are more common in UC than CD | |
| Management | Resection not curative | Colectomy eliminates illness |
| Epid | Develops in teen and twenties | |
| Complications | Intestinal obstruction / perforation | |
| Extraintestinal manifestations | Toxic megacolon! | |
Peak incidence for both is between 15-30 years. Buy disease can occur at any age.
Ileal resection can cause bile acid malabsorption -> diarrhoea.
#2022BSQ BSQ Q49
Source
#2022BSQ Q40
Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.
Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.
(U-100) denotes the usual concentration (100 U/ml).
Duration: Short acting.
Controls post prandial glucose rise.
Same AA sequence as human insulin.
Bound to Zinc.
Hexamers must be converted to dimers and monomer before absorption -> leads to a delay in peak concentrations-> should be given 30 minuted before meals.
Duration of action tends to exceede duration of post prandial glucose rise -> risk of hypoglycaemia.
Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.
mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.
Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.
made by recombinant DNA technology.
Subsitution of amino acids produces rapid acting and long acting analogs.
Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset
modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action
Insulin aspart- substitution of aspartic acid for proline at position B28.
Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.
Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.
Rapid acting insulins are move convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.
Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
Can't mix with rapid acting insulins.
Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.
After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.
Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered
Glargine has less nocturnal hypoglycemia than NPH insulin
Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, it has a small peak in it's concentration profile.
Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.
form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.
Site of injection - Limbs are faster than abdomen. (muscle-> increased blood flow)
NPH insulin - leg or buttock preferred for moderate rate of absorption.
Pre meal regular insulin - abdominal wall preferred for rapid absorption.
The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site
#2022BSQ Q48
Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source
[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]
| Type 1 | Type 2 | Type 3 | Type 4 |
|---|---|---|---|
| commonest type | Goodpasture syndrome, autoimmune anaemias, erythroblastosis faetalis | [[2023-SEMPaper#Systemic Lupus Erythematosus SLE|SLE]], serum sickness, reactive arthritis, PSGN, [[2022 November SBR#Rheumatoid arthiritis|Rheumatoid Arthtiris]] | second most common |
| Immediate hypersensitivity - eg analphylaxis | 2-24 hours | days to weeks | 2 days |
| IgE (from plasma cells) mediated | IgG and IgM - bind to own cell surface molecules -> complement activated | IgG and IgM antigen antibody complexes | Cell mediated - non antibody dependant - T cells, monocytes and macrophages |
| degranulation of mast cells and basophils | complement mediated red cell agglutination and other cell lysis | Cytokines which cause cell death and inflammation are released | |
| Type | Alternate name | Examples | Mediators |
|---|---|---|---|
| I | Allergy (immediate) | • Atopy – Anaphylaxis – Asthma – Allergic rhinitis – Angioedema – Food allergy | IgE |
| II | Cytotoxic, antibody-dependent | • Erythroblastosis fetalis • Goodpasture syndrome • Autoimmune anemias, thrombocytopenias | IgG, IgM |
| III | Immune complex disease | • Systemic lupus erythematosus • Serum sickness • Reactive arthritis • Arthrus reaction | Aggregation of antigens IgG, IgM Complement proteins |
| IV | Delayed-type hypersensitivity, cell-mediated, antibody-independent | • Contact dermatitis • Tuberculosis • Chronic transplant rejection | T cells, monocytes, macrophages |
[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories
Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]
#2022BSQ Q54
[!TIP] Water diarrhoea
Same day:
- Norovirus
- clostridium perfringens
- possibly listeria (pregnancy, immunosuppression, extremes of age)
Next day:
- E coli - enteroroxigenic
- most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults
Same week
- Cyclospora
Weeks later
- Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
- Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools.
[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"
Let's break it down:
- "Can't" - Campylobacter
- "Assume" - Amoebiasis
- "Everyone's" - E. coli
- "Your" - Yersinia
- "Very" - Vibrio parahaemolyticus
- "Special" - Salmonella
- "Sidekick" - Shigella
Most of these have P-incu of 1-3 days. But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.
Main two pathogens of epidemic diarrhoea
Commonest causes of non epidemic watery diarrhoea - E. coli.
[!TIP] mnemonic
Acute bloody diarrhoea
$$
\Large{C^1S^2E^3}
$$
Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)
Pin worm.
Humans are considered the only host for E. vermicularis
Infection is commonest in children and institutionalised people.
Treatment is easy; reinfection is also easy.
Commonest symptom: itching in the perianal area, possible with excoriation and seconday bacterial infection.
Perianal itching / scratching contributes to faeco-oral transmission of the parasite.
Infection of the female genital tract can occur. Can cause abdominal pain mimicking appendicitis.
Treatment: Albendazole, mebendazole
Strongyloides stercoralis : thread worm
First discovered in french troops returning from vietnam in the 19th century who developed chronic diarrhoea.
Infective stage : Filariform larva: -> penetrates intact skin.
[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.
Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.
It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)
Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+)
Ivermectin has been shown to be superior to albendazole.
Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.
Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.
#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.
#2022GM Q14
Pathogenesis: Autoimmune disease affecting exocrine glands.
In most cases, Sjogren syndrome is only 'irritating' and not dangerous.
Can occur as a primary disorder or secondary to another rheumatic disease.
Symptoms are classified mainly as
Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.
Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.
90% are positive for Rheumatoid factors: Kumar and Clark
Epidemiology: Most Commonly occurs in women aged 50-60 years old.
Keratoconjuntivis sicca - term for the occular manifestations of Sojgrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement; Sojgren's disease is one possible cause of this.
Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.
Objective test: Focal lymphocytic sialadenitis score >= 1;
Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.
Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.
Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.
Vascular:
Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.
inhibition of synthesis of NO in rats restores normal arterial pressure.
? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.
mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)
Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.
Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.
A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.
See hypothesis-highlights on UpToDate
#2022GM Q32
Serum 'to' Ascites Albumin gradient
SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)
Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.
#2022GM Q21
Respiratory epithelium - ciliated pseudostratified columnar epithelium.
Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.
Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.
Commoner in women.
Increases with age; marked increase after 60 years.
Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions
Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$
Usually affects bilateral lower lobes.
Permanent dilation -> small airways are traceable almost upto the pleura. (in normal lungs, they stop about 2 cm short of the pleura)
Chronic inflammatory exudate is seen.
Extensive desquamation of epithelium causing ulceration.
Healing is usually by fibrosis.
Abscesses can form as complications.
Clinical and CT:
CT features that are reliable signs of bronchiectasis:
Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.
Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response
Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis
Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection
Primary immunodeficiencies arise from inborn defects. They usually present in childhood.
Common variable immunodeficiency is an notable exception to this.
Seconday immunodeficiency is far more common (?in adult populations)
| Defect | Presentation |
|---|---|
| Ig / complement | Recurrent sinopulmonary infection / meningitis / chronic GI infections (esp. capsulated organisms - H. Influenza, N. meningitidis, S. pneumonae) |
| Granulocyte (neutrophil) defects | Recurrent soft tissue infection |
| Cell mediated immunity (esp. T cells) | Infection with Viruses, intracellular pathogens, fungi (CMV, EBV, mycobacteria, candida, [[HIV-AIDS |
Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
Recurrent abscess formation in the same anatomic location often arises from a local defect, such as a congenital branchial cleft cyst, pilonidal or urachal cyst, hidradenitis suppurativa, or a retained foreign body.
Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction.
However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
Marked elevation of serum IgE with multisystem infections -> Job syndrome
"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".
There are 18 different types of systemic and 22 localized forms of amyloidosis
The four most common causes of systemic amyloid deposition are
[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.
| Type | Constituent |
|---|---|
| AL Amyloidosis | Deposition of Ig Light chain fragments |
| Transthyretin amyloidosis | |
| AA amyloidosis | serum amyloid protein - acute phase reactant; Most common form in resource limited countries - occurs due to chronic inflammation |
Other forms of amyloidosis:
Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.
When congo red stains binds to amyloid protein, it produces apple green birefringence.
Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)
AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)
There is multisystem amyloid deposition
Fatigue, non intentional weight loss
Heavy proteinuria (70%) - nephrotic syndrome
oedema
#hepatosplenomegaly (hepatomegaly +/- splenomegaly seen in 70%)
Cardiomyopathy and heart failure (60%) - thickening of interventricular septum is present / MI due to accumulation of amyloid in coronaries.
Neuropathies - carpal tunnel, mixed sensory and motor peripheral neuropathy is a prominent feature in AL amyloidosis. (Symptoms of numbness, paresthesia, and pain are frequent)
Amyloid infiltration of muscles - macroglossia with scalloping and shoulder pad sign. (also enlarged deltoids)
Skin - purpura (raccoon eyes with valsalva maneuver is specific), waxy skin, easy bruising.
Coagulopathy - possibly due to factor X binding of coagulation factors to amyloid.
GI involvement: gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from *dysmotility
Bortezomi based induction
Melphalan
Haematopoietic cell transplantation.
This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.
The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.
AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.
SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis
In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.
Spondylos = greek for vertebrae
Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis
Sacroiliac joint:
sclerosis,
joint space widening, or erosion (fusion in late stages)
syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.
A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.
Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.
#TODO add image of enthesis
#2022GM Q25
#2022GM Q27
Ankylosing = stiffness or fixation of a joint by disease
Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)
Some terminology: not super important
SourceGreat article!
HLA-B27
[!INFO] Key points
- It's largely a genetic disease - Patient's children have increased risk of getting it
- Pathogenesis consists of inflammation, bone erosion and syndesmophyte formation.
- Bone erosion and syndesmophyte formation are probably not linked to inflammation
- TNF-blockage suppresses symptoms but doesn't arrest bone changes.
#2022GM Q30
Congenital
Acquired
Hepatosplenomegaly and lymphadenopathy are rare.
[!TIP] Overview
Effective anti epileptic but with unpredictable pharmacology and significant toxic effects.
[!SUMMARY] Phenytoin
Phenytoin is a second line antiepileptic (now used mainly in ED settings) with narrow therapeutic window.
It has multiple side effects.
- Acute toxicity can produce motor symptoms.
- Low protein states, uraemia, and liver dysfunction predispose to toxicity.
- Gum swelling, hypertrichosis and idiosyncratic TEN are important side effects
Mechanism:
Phenytoin binds to and inhibits voltage-dependent sodium channels, which are found on both neuronal and cardiac tissue.
0 order / zero order kinetics at therapeutic concentrations (saturation kinetics)
Narrow therapeutic index.
Enzyme inducer.
Valproate displaced phenytoin from bound proteins -> increased risk of toxicity.
Ethanol / Phenobarbital
Used for GTCs.
Complex partial seizures
Status epilepticus
Symptoms : N/V, headache,
motor effects: nystagmus, tremmor, cerebellar ataxia.
10 - 20 - occasional horizontal nystagmus
20 - 30 - nystagmus+
30 - 40 - ataxia, slurred speech, tremmors, NV
40 - 50 - lethargy, confusion and hyperactivity
> 50 mg/L. - Coma and seizures
IV phenytoin can have cardiac effects;
Rare side effect of IV phenytoin : purple glove syndrome: distal oedema of limbs with necrosis.
==Phenytoin worsens primary generalized epilepsies.==
Phenytoin worsens absense seizures and myoclonic seizures.
Supportive; mortality rate is low.
Phenytoin is structurally related to the barbiturates.
[!TIP] left Side - Inhibitors; Right side - INDUCERS,
| Strong inhibitors | Strong inducers |
|---|---|
| Clarithromycin | Carbamazepine |
| Itrakonazole, ketoconazole | Phenytoin |
| Voriconazole | Fosphenytoin |
| Phenobarbital | |
| Rifampicin |
| Moderate inhibitors | Moderate inducers |
|---|---|
| Amiodarone | Bosentan |
| Aprepitant/ fosaprepitatnt | Dexamethasone |
| Cimetidine | St. John's wort |
| Diltazem | |
| Erythromycin | |
| Fluconazole | |
| Verapamil |
The free, unbound portion of a drug can be very small. (1%).
The most important protein which binds drugs is albumin.
Albumin binds many acidic drugs - warfarin, NSAIDS, Sulfonamides.
and fewer basic drugs (TCA, chlropromazine).
For most drugs at therapeutic concentration, the carrier proteins very far from saturated.
At these concentrations, bound fraction does not changes with drug concentration.
However, tolbutamide almost completely saturates proteins at therapeutic level. So increasing dose increases the free proportion disproporionately.
Sulfonamides have very high affinity so they occupy about 50% of the binding sites on albumin. This allows sulfonamides to significantly displace other protein bound drugs.
From DerangedPhysiology:
Selected drugs which are highly protein bound
Source
Initially developed as antibacterials; not used much now for that role (because of resistance) except for
Non antibacterial sulfonamides
There are antimicrobial and non antimicrobial sulfonamides: There's a large list!
List
Sulfonamide-containing nonantimicrobial agents (Table 1) include agents from therapeutic classifications such as thiazide and loop diuretics, carbonic anhydrase inhibitors, nonsteroidal anti-inflammatory drugs, sulfonylureas, antiretrovirals, and 5HT-3 receptor agonists
In the general population, approximately 3–8% of patients are reported to experience a sulfonamide allergy.
Stevens-Johnson syndrome can occur.
[!INFO] Allergy
Although many types of drugs have the NH2-SO2 sulpha group and are therefore technically 'sulfa-drugs', they don't have some additional group which are responsible for the allergies caused by the antibacterial sulphonamides. Therefore, cross reactivity and allergy risk is low.
The nonantimicrobial sulfonamides do not undergo metabolism to the N4-hydroxylated metabolite associated with SJS and will not bind to IgE at the N1 position and, therefore, are unlikely to cause cross-reactivity, even in patients who have experienced type 1 hypersensitivity or serious non-type-1 hypersensitivity reactions to sulfonamide antimicrobial agents.
A few known drugs show zero order / 0 order kinetics.
==Most drugs show first order kinetics==.
ChatGPT: (verified)
Important implications for saturation kinetics:
Illustration of the difference of variation in plasma concentration between zero and first order kinetics:
Phenytoin is the classical poster child for non-linear elimination kinetics, because the enzyme saturation point is reached somewhere in the middle of the therapeutic concentration range - Deranged Physiology
1/3 of patients have chronic hepatitis B infection.
11. Somehow, lungs aren't involved.
[!TIP] Mnemonic

1. GPA (Granulomatosis with polyangitis) - Wegener's ganulomatosis
2. EGPA (**Eosinophilic** granulomatosis with polyangiitis)- Churg Strauss syndrome
3. MPA (Microscopic polyangitis) - no other name.
[!INFO] Types of ANCA antibodies
It was found that the serum of patients with vasculitis would stain neutrophils in one of two pattersn:
- Perinuclear - this serum has p-ANCA antibodies
- Cytoplasmic - this serum has c-ANCA antibodies.
C-ANCA stains neutrophil proteinsase 3 (PR3 ANCA = cANCA)
P-ANCA stains neurtrophil myeloperoxidase (MPO ANCA = pANCA)
c in C3PO and 3 is also in C3POpANCA - MPA and EGPA
cANCA - GPA
" c " in c-ANCA looks like " G " in GPA.